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Structure of a complex between a voltage-gated calcium channel β-subunit and an α-subunit domain

Nature volume 429, pages 671–675 (2004)Cite this article

Abstract

Voltage-gated calcium channels (CaVs) govern muscle contraction, hormone and neurotransmitter release, neuronal migration, activation of calcium-dependent signalling cascades, and synaptic input integration1. An essential CaV intracellular protein, the β-subunit (CaVβ)1,2, binds a conserved domain (the α-interaction domain, AID) between transmembrane domains I and II of the pore-forming α1 subunit3 and profoundly affects multiple channel properties such as voltage-dependent activation2, inactivation rates2, G-protein modulation4, drug sensitivity5 and cell surface expression6,7. Here, we report the high-resolution crystal structures of the CaVβ2a conserved core, alone and in complex with the AID. Previous work suggested that a conserved region, the β-interaction domain (BID), formed the AID-binding site3,8; however, this region is largely buried in the CaVβ core and is unavailable for protein–protein interactions. The structure of the AID–CaVβ2a complex shows instead that CaVβ2a engages the AID through an extensive, conserved hydrophobic cleft (named the α-binding pocket, ABP). The ABP–AID interaction positions one end of the CaVβ near the intracellular end of a pore-lining segment, called IS6, that has a critical role in CaV inactivation9,10. Together, these data suggest that CaVβs influence CaV gating by direct modulation of IS6 movement within the channel pore.

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Figure 1: Structure of the CaVβ2a–CaV1.2 AID complex.
Figure 2: Structural comparisons between PSD-95 (gold) and CaVβ2a (blue).
Figure 3: Features of the AID–CaVβ2a interaction and location of the previously described BID.
Figure 4: AID–ABP interactions.
Figure 5: Cartoon of proposed model for how CaVβ affects CaVα1 gating.

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Acknowledgements

We thank J. M. Berger, K. Brejc, D. Fass, D. Julius, E. A. Lumpkin and B. A. Schulman for comments on the manuscript; J. Holton at beamline 8.3.1 at the Advanced Light Source for help with data collection; R. W. Tsien and D. T. Yue for the calcium channel clones; and members of the Minor laboratory for support at all stages of this work. This work was supported by awards to D.L.M. from the McKnight Foundation for Neuroscience, the March of Dimes Basil O'Connor Scholar program, the Alfred P. Sloan Foundation, and the Rita Allen Foundation. D.L.M. is a McKnight Foundation Scholar, an Alfred P. Sloan Research Fellow and a Rita Allen Foundation Scholar.

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  1. Cardiovascular Research Institute, Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California San Francisco, 513 Parnassus Avenue, Box 0130, California, 94143, San Francisco, USA

    Filip Van Petegem, Kimberly A. Clark, Franck C. Chatelain & Daniel L. Minor Jr

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  1. Filip Van Petegem
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Correspondence to Daniel L. Minor Jr.

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Supplementary information

Supplementary Information

Includes Supplementary Figure 1: Schematic representation of interactions between the AID peptide and Cavβ2a; Supplementary Figure 2: Location of AID residues implicated in Gβγ binding; Supplementary Table 1: Data collection, phasing and refinement; Supplementary Table 2: Accessibilities of AID residues in the AID-CaVβ2a complex; Supplementary Methods; Supplementary References. (PDF 419 kb)

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Van Petegem, F., Clark, K., Chatelain, F. et al. Structure of a complex between a voltage-gated calcium channel β-subunit and an α-subunit domain. Nature 429, 671–675 (2004). https://doi.org/10.1038/nature02588

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